Abstract 11579: Essential Role of Nitric Oxide Synthase in Caloric Restriction-Induced Cardioprotection
BACKGROUNDS: Increasing evidence demonstrates that caloric restriction (CR) confers cardioprotection against ischemia (I) /reperfusion (R) injury. We demonstrated that chronic inhibition of nitric oxide synthase (NOS) by L-NAME completely abrogated CR-induced cardioprotection, but it was unclear which NOS isoform is essential for CR-induced cardioprotection because L-NAME is a non-selective NOS inhibitor.
METHODS: We subjected 3-month-old male mice in which each NOS isoform was selectively disrupted to either ad libitum (AL)-feeding or CR (-40%) for the next 3 months. Isolated perfused hearts were subjected to 25 min of global I, followed by 60 min of R.
RESULTS:(Figure) (1) The cardioprotection was induced with CR in iNOS-/- as observed in Wild-type mice (Wt). However, CR failed to exert cardioprotection in nNOS-/-. The degree of myocardial I/R injury in AL-fed eNOS-/- was worse than that in AL-fed Wt. The coronary flow during R was significantly lower in eNOS-/- and this was responsible for the relatively low value in total LDH release in eNOS-/-. CR did not exert cardioprotection in eNOS-/-. (2) The eNOS-/- exhibited elevated blood pressure (BP) and increased LV weight/body weight, compared with Wt, even though they were treated with CR. To exclude the influence of elevated BP on the development of CR-induced cardioprotection, twelve eNOS-/- were treated with hydralazine (H) for 3 months. As a result, BP and LV weight/body weight became comparable with CR-treated Wt, but CR-induced cardioprotection was not observed. (3) The increase in Sirt1 in the nuclear fraction was absent in eNOS-/-, but it was observed in nNOS-/- as seen in Wt.
CONCLUSIONS: These results demonstrate that (1) nNOS and eNOS are essential for CR-induced cardioprotection, (2) the essential role of eNOS is independent of its hemodynamic effect, and (3) eNOS is located upstream of Sirt1 activation in CR-induced cardioprotection. However, the relationship between nNOS and Sirt1 remains to be resolved.
- © 2011 by American Heart Association, Inc.